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Tebipenem pivoxil, an oral carbapenem prodrug, was launched in Japan in 2009 by Meiji Seika Pharma for the treatment of bacterial infection in children. The drug candidate was originally developed at Wyeth Pharmaceuticals (now Pfizer) and was subsequently licensed to Meiji Seika.

Tebipenem pivoxil was approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Apr 22, 2009. It was developed and marketed as Orapenem® by Meiji Seika in Japan.

In 2017, the product was licensed to Spero Therapeutics by Meiji Seika Pharma for worldwide development and commercialization, except in Japan and certain Asian countries, where Meiji will retain rights.

Tebipenem pivoxil is a broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. Carbapenems are a class of beta-lactam antibiotics, which act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. It is used to treat otorhinolaryngological infection, otitis media and bacterial pneumonia.

Orapenem® is available as granules for oral use, containing 100 mg Tebipenem pivoxil/g granules. According to the weight of children, 4 mg/kg, and twice a day after dinner.

[0004] developed by the American company Pfizer, for Bipei Nan ester fine granules developed by the Japanese company Meiji, in February 2009 was approved in Japan, and listed in April 2009.Alternatively Bipei Nan prodrug esters are for Bipei Nan, the lower the water after oral administration of the parent drug esterase for Bipei Nan, penicillin-binding protein binding to bacteria (the PBP), inhibition of bacterial cell wall synthesis, and is the only can oral carbapenem antibiotics.

[0005] Alternatively esters Bipei Nan structural characteristics, is a C3-side chain is thiazolyl substituted azetidinyl group, while in the C2 position by matching volts carboxylic ester forming a prodrug, increased oral absorbability; its oral absorption is better than in most β_ lactam antibiotics already on the market now.Bipei Nan for a broad spectrum antibiotic; especially for the PRSP in recent years, mainly due to the infection caused by children (penicillin-resistant Streptococcus pneumoniae), MRSP (erythromycin-resistant Streptococcus pneumoniae) and Haemophilusinfluenzae (Haemophilus influenzae) showed a very strong antibacterial effect.Alternatively Bipei Nan as prodrugs compared to for Bipei Nan horses volts for Bipei Nan ester having a better absorption kinetics, has good stability.

[0006] TakeshiIsoda like literature SynthesesandPharmacokineticStudiesof ProdrugEstersfortheDevelopmentofOralCarbapenem, L-084 (TheJournalof Antibiotics (2006) 59, 241 – 247; doi:. 10 · 1038 / ja 2006. 34) discloses a method for the synthesis of ester Bipei Nan : the Bipei Nan Alternatively, benzyltriethylammonium chloride, and chloromethyl pivalate was dissolved in N, N- dimethylformamide was added a solution of N, N- diisopropylethylamine, in the reaction was stirred for 4h at 45 ° C, the reaction was cooled to complete 5 ° C, was added ethyl acetate and water, the mixture was adjusted with aqueous citric acid I.OM PH = 4, the organic phase was discarded, the aqueous phase was adjusted with potassium bicarbonate to PH = 7. 6, the mixture extracted with ethyl acetate, the organic phase was washed with water and aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, the residue was subjected to silica gel column to give a yellow solid which was slurried with ethyl acetate to give colorless crystals.The column chromatography method requires not only consume a large amount of organic solvent together IJ, and a long time, so this method is not suitable for industrial production. In addition, the resulting large solid slurried with ethyl acetate, a solid dispersion is not easy, affect the uniformity of the product.

[0007] Patent US5534510, EP0632039, JP10-195076 discloses a method for synthesizing Bipei Nan ester is: dissolved after lyophilization for Bipei Nan aqueous sodium bicarbonate, lyophilized solid was dissolved in N, N- two dimethylformamide, adding a specific acid, methyl iodide, LH stirred at room temperature, ethyl acetate was added the reaction was completed, the organic phase was washed with saturated aqueous sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, the solvent was removed, the residue was subjected Alternatively Bipei Nan silica gel column to give the ester.The Mr. Fang Fati Bipei Nan for Bipei Nan into the sodium salt of pivalic acid with methyl iodide, prior to lyophilization to remove water required for the reaction, or affect the subsequent reaction with methyl iodide pivalate, lyophilized difficult when enlarged and the operation will take longer, the method further column chromatography operations shall therefore not suitable for industrial production.

Halogenation of allylamine (I) with either bromine or sulfuryl chloride produced the corresponding (halomethyl)aziridines (II). Subsequent treatment of (II) with n-butyllithium at -78 C yielded 1-azabicyclobutane (III). Opening of the bicyclic system of (III) with formic acid followed by acid hydrolysis provided 3-hydroxyazetidine (IV). This was condensed with 2-(methylsulfanyl)thiazoline (V) to give thiazolinylazetidine (VI). Alternatively, 3-hydroxyazetidine (IV) was condensed with 2-chloroethyl isothiocyanate (VII) to give the intermediate thiourea (VIII), which cyclized to the thiazoline (VI). Conversion of the hydroxyl group of (VI) into the thioacetate (IX) was carried out by either coupling with thioacetic acid under Mitsunobu conditions or by conversion to mesylate (X) followed by displacement with potassium thioacetate. The required thiol (XI) was then obtained from (IX) by basic hydrolysis of the thioacetate ester.

1-azabicyclobutane (III) was opened with thioacetic acid with concomitant N-acetylation yielding (XII). Further acid hydrolysis of (XII) gave 3-mercaptoazetidine (XIII). Condensation of (XIII) with either 2-(methylthio)thiazoline (V) or 2-chloroethyl isothiocyanate (VII) then produced thiazolinylazetidine (XI).

A further procedure consisted in the opening of 1-azabicyclobutane (III) with 2-mercaptothiazoline (XIV) to give (XV). Subsequent rearrangement of (XV) in the presence of methanesulfonic acid produced thiazolinyl azetidine (XI).

Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford the target carboxylic acid.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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